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Insomnia – conceptualization and management in 2009. Martin Reite MD Clinical Professor of Psychiatry Medical Director, Neuromagnetic Imaging Lab UCHSC. What we are going to talk about:. Neurophysiology of sleep Process S and Process C Functions of sleep Effects of sleep loss

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Insomnia – conceptualization and management in 2009

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Insomnia – conceptualization and management in 2009

Martin Reite MD

Clinical Professor of Psychiatry

Medical Director, Neuromagnetic Imaging Lab


What we are going to talk about:

  • Neurophysiology of sleep

  • Process S and Process C

  • Functions of sleep

  • Effects of sleep loss

  • What are the insomnia disorders?

  • How do we go about a differential diagnosis?

  • What treatment options are available and how, when, and how long do you use them?

Arousal control systems

BF basal forebrain

LC locus coeruleus

LDT laterodorsal tegmental

LHA lateral hypothalamus

PPT pediculopontine

TMN tuberomammillary

Saper et al. Nature 437:27, 2005

Sleep control systems

VLPO ventrolateral preoptic nucleus

ORX orexin neurons

Saper et al. Nature 437:27, 2005

Orexin modulated flip-flop switch

Awake state

Sleep state

Saper et al. Nature 437:27, 2005

Histamine and wake/sleep regulation

  • Histamine in CSF decreased in narcolepsy and primary hypersomnia

  • Three receptor subtypes:

  • H1 & H2 widespread in brain as well as peripheral – postsynaptic and promote excitatory neurotransmission & wakefulness – antagonists promote sleep

  • H3 presynaptic in brain – activation decreases histamine release and promotes sleep – antagonists promote wakefulness

  • Histaminergic neurons in tubero-mammilary nucleus (TMN) of post hypothalamus

  • Hypocretin neurons project to and regulate TMN histamine production via hcrt-2 receptor subtype

Kanbayashi et al Sleep 32:181, 2008Nishino et al Sleep 32:175. 2008

Sleep stages and their function

  • General purpose of sleep is maintenance of brain function. Total sleep deprivation leads to death.

  • Non-REM slow wave sleep, especially Stage 3-4 (delta) sleep may be involved in synaptic “pruning” and “tuning” and other aspects of learning and memory

  • REM sleep essential for the developing mammalian brain, but functions of REM sleep in adults remains uncertain

Consquences of sleep loss in normal subjects

  • ↓ psychomotor performance

  • ↓ antibody performance following immunization*

  • ↓ leptin and↑ grehlin production**

  • ↑ C-reactive protein***

  • ↑ risk for insulin resistance and type 2 diabetes

  • Chronic insomniacs may be at increased risk for all the above

*Lange et al Psychosom Med 65:831, 2003

**Spiegel et al Ann Int Med 141:846, 2005*

***Meier-Ewert et al J Am Coll Cardiol 43:678, 2004

Insomnia – the most common sleep complaint

30% of people in the general population experience symptomsconsistent with insomnia

Symptoms may include:

Cant get to sleep, cant stay asleep, wake to early, sleep not refreshing, all of the above

Consequences of chronic insomnia

Diminished quality of life, impaired memory and concentration, ↓ ability to accomplish daily tasks, ↓ ability to enjoy interpersonal relationships

↑ risk of developing anxiety and depression*

↑ health care costs

Impaired memory consolidation

↓ hippocampal volumes** (?memory?)

*Neckelmann et al Sleep 30:873, 2007

**Riemannn et al Sleep 30:955, 2007

Differential Diagnosis of a chronic insomnia complaint - a 6 step process


Step 1. Medical conditions and dementia

Step 2. Psychiatric disorders

Step 3. Substance misuse

Step 4. Circadian rhythm disorders

Step 5. Movement disorders including Restless leg syndrome (RLS) and Periodic Leg Movements in Sleep (PLMS)

Step 6. The primary insomnia, conditioned insomnia and SSMP group

Primary insomnia

Conditioned insomnia

Sleep State Misperception Syndrome (SSMS)

From Reite, Weissberg & Ruddy, Clinical Manual for the Evaluation and Treatment of Sleep Complaints APA Press, 2009

Common circadian rhythm disorders

Delayed sleep phase syndrome

  • most common – usually familial/genetic causes

  • Onset adolescence & early adulthood

  • Advanced sleep phase syndrome

    • Onset late adulthood

    • Both familial and age related causes

  • Non-24 hour sleep wake rhythm

    • Seen in 50% of blind persons

    • Also seen in developmental disorders

All masquerade as “insomnia”

Circadian Rhythm with a 24 Hour Period

6 Hour Delay of the Circadian Rhythm – phase delay

Free-running Circadian Rhythm

6 AM

6 AM

6 AM

6 AM

6 AM

Alterations in the Circadian Rhythm

Diagnosis of circadian rhythm disorders

  • History

  • Actigraphy

  • Polysomnography usually not helpful

Actigraphy in DSPD

Treatment of circadian rhythm disorders

  • Light treatment at appropriate time

  • Appropriately timed melatonin

  • Strict sleep schedule

  • Limited use of hypnotics

The Primary Insomnia, Conditioned Insomnia, Sleep State Misperception (Paradoxical Insomnia) Group – often termed “psychophysiological insomnia”

  • Primary Insomnia a DSM-4 diagnosis

  • Difficulty initiating, maintaining, or non restorative sleep >1mo

  • Causes significant daytime functional impairment

  • Other med, psych, circadian causes ruled out

  • Conditioned or “Learned” insomnia

  • Starts with stressful situation impairing sleep

  • Fears going to bed because wont be able to sleep

  • May sleep normally in other places e.g. sleep lab

  • Sleep state misperception syndrome

  • Unaware of being asleep

  • May have “normal” PSG in lab (yet complain of not sleeping)

  • Daytime impairment similar to primary insomnia

  • Termed “paradoxical insomnia”

Treating Insomnia Requires a Comprehensive Approach


Treat Underlying Causes

Relieve Symptoms

Modify Behavior


  • Pharmacotherapy

  • Patient education

  • Reconditioning to improve sleep hygiene

  • Pain management

  • Psychotherapy

  • Medical specialists

  • Sleep specialists

  • Review medications


  • Primarily for short-term treatment

  • Restore restful sleep while other modalities implemented

  • Longer term effect

  • Restore/establish good sleep hygiene

  • Prevent chronic insomnia

  • Long term goal

  • Reduce/eliminate sleep disruption caused by other conditions

Nonpharmacologic Treatment Strategies

Cognitive behavioral therapy very important

  • Sleep education

  • Sleep hygience education

  • Sleep restriction

  • Relaxation training

    Biofeedback may be helpful

    Exercise & improved aerobic fitness

    But – pharmacoloigcal treatments will usually also be necessary

Other sleep agents -1

Tiagabine (Gabitril) inhibits GABA reuptake, approved for seizure control only – improved sleep in chronic pain (Todorov et al, 2005), increases SWS in dose dependent fashion 4-10 mg (Walsh 2006)

Sodium oxybate (Xyrem) – approved for narcolepsy – increases Stage 3-4 sleep – considerable potential risk – one of the date rape drugs (GHB, flunitrazepam, ketamine) – may be useful in fibromyalgia (Scharf et al 2003)

Todorov et al Clin J Pain 21:358, 2005

Walsh et al J Clin Sleep Med 2:35, 2006

Scharf et al J Rheumaton 30:1070, 2003

Other sleep agents - 2

Gaboxadol – selective extrasynaptic GABAa agonist increases SWS dose dependent up to 15mg (Deacon et al 2007)

Doxepin effective for primary insomnia at 3 and 5 mg (Roth et al 2007)

Ramelteon (Rozerem) – M1 & M2 melatonin receptor agonist - role still uncertain in insomnia but is approved for long term use– probably circadian rhythm control

Deacon et al Sleep 30:281, 2007

Roth et al Sleep 30:1555, 2007

Other Sedating Antidepressants and Prescription Medications Used Off-label

Sedating antidepressants

Mirtazapine, doxepin and amitriptyline are used but with little supporting data except for doxepin

The NIH panel raised concerns about the risk-benefit ratio due to the associated adverse effects

Antipsychotics (eg, quetiapine and olanzapine) and barbiturates

The NIH panel concluded that these classes lack the data for use in insomnia and were not recommended due to significant risks associated with treatment

National Institutes of Health. NIH state-of-the-science conference statement: manifestations and management of chronic insomnia in adults. June 13-15, 2005. Available at

Benzodiazepine Receptor Agonists NIH Panel Conclusions

  • Benzodiazepines

    • Estazolam, flurazepam, quazepam, temazepam, and triazolam

  • Nonbenzodiazepines

    • Eszopiclone, zaleplon, and zolpidem

  • Both classes are indicated for treating insomnia, but the risk-benefit ratio for nonbenzodiazepines is superior to that of the benzodiazepines

  • Efficacious for short term treatment

    • Eszopiclone has been studied for 6 months and is approved for use without a specified time limit

    • Extended release zolpidem has been studied for 3 weeks and does not have a specified limit to treatment duration1

  • No evidence of tolerance or abuse during short-term treatment in adult and/or elderly patients

National Institutes of Health. NIH state-of-the-science conference statement: manifestations and management of chronic insomnia in adults. June 13-15, 2005. Available at

1Extended release zolpidem package insert, 2005.



Stage 1

Stage 2

Stage 3

Stage 4









Comparison of Sleep Cycles in Young Adults and the Elderly



Stage 1

Stage 2

Stage 3

Stage 4

Young Adults









Hours of Sleep


Hours of Sleep

The elderly tend to have less stage 3 and 4 sleep and develop advanced phase sleep syndrome (go to bed early, wake up early), while the young tend to have delayed phase shift syndrome (go to bed late, wake up late).

Neubauer DN. Am Fam Physician. 1999;59:2551-2558.

Millman RP, Working Group on Sleepiness in Adolescents/Young Adolescents. Pediatrics. 2005;115:1774-1786.

Sleep and aging

  • Multiple med/psych/environ causes for insomnia

  • Process S – 50% loss of VLPO neurons with age

  • Process C – decreased melatonin production and decreased light sensitivity with age

  • Does sleep loss and fragmentation in the elderly contribute to many of the symptoms attributed to “normal” aging – e.g. cognitive difficulties, inflammation, weight/diabetes?

  • Where do we stand with respect to long term hypnotic use to improve sleep in otherwise healthy older adults?

  • What about hypnotic use and falls?

Insomnia, hypnotics, and falls in the elderly

  • In 34,163 nursing home residents in Michigan, complaints of insomnia (past month), but not hypnotic use (past week) predicted falls. Untreated insomnia, and hypnotic unresponsive insomnia, primarily responsible for falls.

  • Avidan et al J Am Geriatr Soc 53:955, 2005

Overall Summary

  • Sleep complaints should be taken seriously

  • Accurate differential diagnosis important

  • Sleep studies usually for EDS disorders

  • Sleep studies usually not needed for insomnia

  • Safe and effective treatments available for most insomnias

  • Long term treatment may be necessary for insomnia as in depression

  • Don’t neglect behavioral (eg CBT) treatments

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